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. 2013 Nov;27(6):478-85.
doi: 10.7555/JBR.27.20130021. Epub 2013 Sep 25.

Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients

Xiaojian Ni  1 , Yingchun Zhao, Jingjing Ma, Tiansong Xia, Xiaoan Liu, Qiang Ding, Xiaoming Zha, Shui Wang
Affiliations

Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients

Xiaojian Ni et al. J Biomed Res. 2013 Nov.

Abstract

Hypoxia-induced factor-1 alpha (HIF-1α) affects many effector molecules and regulates tumor lymphangiogenesis and angiogenesis during hypoxia. The aim of this study was to investigate the role of HIF-1α in the regulation of vascular endothelial growth factor C (VEGF-C) expression and its effect on lymphangiogenesis and angiogenesis in breast cancer. Lymphatic vessel density (LVD), microvessel density (MVD) and the expressions of HIF-1α and VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples. There was a significant correlation between HIF-1α and VEGF-C (P = 0.014, r = 0.273, Spearman's coefficient of correlation). HIF-1α and VEGF-C overexpression was significantly correlated with higher LVD (P = 0.003 and P = 0.017, respectively), regional lymph nodal involvement (P = 0.002 and P = 0.004, respectively) and advanced tumor, node, metastasis (TNM) classification (P = 0.001 and P = 0.01, respectively). Higher MVD was observed in the group expressing higher levels of HIF-1α and VEGF-C (P = 0.033 and P = 0.037, respectively). Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1α and VEGF-C. HIF-1α was also found to be an independent prognostic factor of overall survival in multivariate analysis. The results suggest that HIF-1α may affect VEGF-C expression, thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer. This study highlights promising potential of HIF-1α as a therapeutic target against tumor lymph node metastasis.

Keywords: HIF-1α; VEGF-C; angiogenesis; breast cancer; lymphangiogenesis.

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Conflict of interest statement

The authors reported no conflict of interests.

Figures

Fig. 1
Fig. 1. HIF-1α and VEGF-C expression in breast carcinoma.
A: High HIF-1α immunoreactivity in the nuclei of cancer cells (magnification×200). B: VEGF-C was expressed in the cytoplasm of breast carcinoma cells (magnification×200).
Fig. 2
Fig. 2. Immunohistochemical staining of D2-40 and CD31.
A: Immunoreactivity of D2-40 proteins was observed in the cytoplasm and cellular membrane of lymphatic endothelial cells (magnification×200). D2-40 expression was restricted to thin-walled lymphatic vessels containing no red blood cells (arrows). D2-40-positive cells were largely distributed in peritumoral tissue (hot spot). B: Representative sections showing CD31+ staining in blood microvessels/endothelial cells (magnification×400).
Fig. 3
Fig. 3. Box-blot showing statistically significant association between lymphatic vessel density (LVD), microvessel density (MVD), and HIF-1α-expression.
A, B, C, and D: P = 0.003, P = 0.033, P = 0.017, P = 0.037, respectively, Mann-Whitney test.
Fig. 4
Fig. 4. Kaplan-Meier overall survival curves for 75 patients with breast carcinoma.
A: Patients with high HIF-1α expression had a significantly worse overall survival (OS) than patients with low HIF-1α expression (P = 0.045). B: Patients with high levels of VEGF-C expression had a significantly worse OS than those with low levels of VEGF-C expression (P = 0.043).
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